[unreadable] Project Summary: [unreadable] Our studies and others have shown that cellular differentiation is inhibited under hypoxic conditions. In some stem cell compartments, such as the bone marrow, the physiological level of oxygenation is much lower than in other tissues under normal physiological conditions, suggesting that hypoxia may play an important role in the regulation of stem cell maintenance and differentiation. However, the role of hypoxia in the regulation of stem cell maintenance still remains unidentified. I propose to investigate the mechanisms by which hypoxia maintains stemnness and regulates other stem cell functions. I am trained as a cancer biologist and have been studying the biology of tumor hypoxia. I was among the first to investigate the role of the hypoxia signaling pathway in the regulation of cellular differentiation. I wish to use my expertise in hypoxia biology to study the maintenance of stem cells by their microenvironment and eventually to extend my career into stem cell research. To achieve this goal, I will first receive training in stem cell research under the tutelage of Dr. Diane Krause, a leading expert in hematopoietic stem cell (HSC) biology. During the K18 Award period, I will learn the basics of HSC and progenitor cell biology and master all of the key techniques while I investigate the role of hypoxia in the maintenance and homing of HSCs. After the training, will continue collaboration with Dr. Krause and other stem cell experts to delineate mechanisms underlying how hypoxia may act to regulated HSCs. I will use the knowledge gained to investigate the role of hypoxia in the regulation of other adult and/or embryonal stem cells. I also wish to develop new technologies for long term maintenance of stem cells in vitro for clinical applications. Yale University has created an excellent environment for stem cell research, and I look forward to becoming a part of Yale's rapidly growing Stem Cell Program. The overall environment is excellent for my training and career development. [unreadable] Relevance to public health: This research could lead to improved methods for the ex vivo growth and maintenance of HSCs long term and thus could facilitate the use of HSCs in stem cell therapies for cancers and other genetic diseases. In addition, discoveries regarding the in vivo microenvironment for HSCs could lead to improved engraftment following hematopoietic stem cell transplantation. [unreadable] [unreadable]